Diabetes Care

Acute Kidney Injury Predicts

Major Adverse Outcomes in
Diabetes: Synergic Impact With
Low Glomerular Filtration Rate
and Albuminuria

Mathilde Monseu,1,2,3,4 Elise Gand,4

Pierre-Jean Saulnier,1,2,3
Stephanie Ragot,1,2,3 Xavier Piguel,4
Philippe Zaoui,5,6 Vincent Rigalleau,7
Richard Marechaud,4,8 Ronan Roussel,9,10
Samy Hadjadj,1,2,3,4,8,11 and
Jean-Michel Halimi,12,13 for the
SURDIAGENE study group

DOI: 10.2337/dc15-1222

OBJECTIVE

Subjects with diabetes are prone to the development of cardiovascular and noncardiovascular complications. In separate studies, acute kidney injury (AKI), albuminuria, and low estimated glomerular ltration rate (eGFR) were shown to
predict adverse outcomes, but, when considered together, their respective prognostic value is unknown.
RESEARCH DESIGN AND METHODS

RESULTS

Intrahospital AKI occurred in 411 of 1,371 patients during the median follow-up
period of 69 months. In multivariate analyses, AKI was signicantly associated
with cardiovascular and noncardiovascular death, including cancer-related death.
In multivariate analyses, AKI was a powerful predictor of major adverse cardiovascular events, heart failure requiring hospitalization, myocardial infarction,
stroke, lower-limb amputation or revascularization, and carotid artery revascularization. AKI, eGFR, and albuminuria, even when simultaneously considered in
multivariate models, predicted all-cause and cardiovascular deaths. All three renal biomarkers were also prognostic of most adverse outcomes and of the risk of
renal failure.

Universite de Poitiers, CIC1402, Poitiers, France

Centre dInvestigation Clinique, CHU de Poitiers,
Poitiers, France
3
INSERM, CIC1402, Poitiers, France
4
Service dEndocrinologie, CHU de Poitiers, Pole
DUNE, Poitiers, France
5
Service Nephrologie, Dialyse et Transplantation,
CHU de Grenoble, La Tronche, France
6
Faculte de Medecine, Domaine de la Merci, Universite Joseph Fourrier, Grenoble, France
7
Service dEndocrinologie, Diabe tologie, Maladies Metaboliques et Nutrition, CHU de Bordeaux, Pessac, France
8
Faculte de Medecine et Pharmacie, Universite
de Poitiers, Poitiers, France
9
Universite Paris 7 Denis Diderot, U695, Paris,
France
10
Service dEndocrinologie, Diabetologie, Nutrition, Groupe Hospitalier Bichat Claude Bernard,
Assistance Public-H o pitaux de Paris, Paris,
France
11
INSERM, U1082, Poitiers, France
12
Service de Nephrologie, CHU de Tours, Tours,
France
13
Universite Franois-Rabelais, EA4245, Faculte
de Medecine, Tours, France
2

Corresponding author: Jean-Michel Halimi,

halimi@med.univ-tours.fr.
Received 6 June 2015 and accepted 24 September 2015.

CONCLUSION

AKI, low eGFR, and elevated albuminuria, separately or together, are compelling
biomarkers of major adverse outcomes and death in diabetes.
Patients with diabetes are prone to the development of cardiovascular and renal
complications (1). In addition, it was shown that infections and cancers develop in
patients with diabetes more frequently than patients without diabetes (2,3). Abnormal albuminuria and low estimated glomerular ltration rate (eGFR) are risk

This article contains Supplementary Data online

at http://care.diabetesjournals.org/lookup/
suppl/doi:10.2337/dc15-1222/-/DC1.
S.H. and J.-M.H. contributed equally to this work.
2015 by the American Diabetes Association.
Readers may use this article as long as the work is
properly cited, the use is educational and not for
prot, and the work is not altered.

Diabetes Care Publish Ahead of Print, published online October 28, 2015

PATHOPHYSIOLOGY/COMPLICATIONS

Patients with type 2 diabetes consecutively recruited in the SURDIAGENE cohort

were prospectively followed up for major diabetes-related events, as adjudicated
by an independent committee: death (with cause), major cardiovascular events
(myocardial infarction, stroke, congestive heart failure, amputation, and arterial
revascularization), and renal failure (i.e., sustained doubling of serum creatinine
level or end-stage renal disease).

Acute Kidney Injury and Outcomes in Diabetes

factors for renal and cardiovascular

complications (4,5). More recently, the
development of acute kidney injury
(AKI) was shown to predict subsequent
renal failure and cardiovascular events
in selected populations (68).
However, to date, our understanding
of the actual prognostic value of AKI in
subjects with diabetes is limited. There
is no comprehensive evaluation of the
prognostic value of AKI with regard to
major complications in nonselected patients with diabetes. Moreover, our vision may be blurred by the fact that AKI
occurs more frequently in patients with
low eGFR and/or albuminuria, both of
which are situations associated with
deleterious outcome (9).
In the current study, we prospectively
assessed the long-term prognostic value
of in-hospital AKI in addition to albuminuria and low eGFR in a large population
of patients with type 2 diabetes. We
specically analyzed whether AKI, low
eGFR, and albuminuria, when considered
alone or together, were global prognostic
factors for death, major vascular events,
or major renal events, and therefore
whether these markers could be used as
renal sensors of global outcome.
RESEARCH DESIGN AND METHODS
Study Protocols and Patient Selection

The present analyses include the subjects recruited in the SURDIAGENE

(SURvie, DIAb`ete de type 2 et GENEtique)
study (10). This French monocentric inception cohort of patients with type 2
diabetes regularly attending the Diabetes Department at Poitiers University
Hospital, France, between 2002 and
2011 included patients with stable conditions whose diet was stable. Patients
considered for the present analysis had a
conrmed diagnosis of type 2 diabetes,
and had not undergone renal replacement therapy (renal transplantation or dialysis) at study inclusion. Biopsy-proven
IgA nephropathy (or other primary glomerular diseases) was an exclusion criterion in the SURDIAGENE cohort.
The design of this study was approved
by the University Hospital Ethic Committee. All participants gave their written
informed consent.
Clinical and Biological Measurements

Blood samples and second morning

urine samples were obtained from patients after an overnight fast. Serum

Diabetes Care

creatinine level was measured using

the Jaffe method. Albuminuria was measured by nephelometry. Urinary albumin-to-creatinine ratio (uACR) was
calculated. eGFR was calculated using
the Chronic Kidney Disease Epidemiology formula (11).
Albuminuria categories were dened
as follows: normoalbuminuria (uACR
,3 mg/mmol), microalbuminuria (uACR
$3 to #30 mg/mmol), and macroalbuminuria (uACR .30 mg/mmol).
The following clinico-biological data,
including personal medical history, were
collected at baseline: myocardial infarction, stroke, peripheral artery revascularization and limb/thigh amputation,
diabetes duration, smoking status,
blood pressure, height, weight, and
medications used. Heart rate was computed using a baseline patient electrocardiogram.
Denition of AKI

AKI (during follow-up) was diagnosed

and staged using the KDIGO criteria
(12). Only serum creatinine criteria
were used to diagnose and stage AKI,
and, therefore, urinary output criteria
were omitted. We considered the lowest creatinine value found between the
dates of hospital admission and discharge as the reference creatinine
value. We identied and classied AKI
by comparing the highest creatinine value
found during full hospitalization to the
reference serum creatinine value. AKI
was dened as a serum creatinine level
of .150% or $0.3 mg/dL ($26.5 mmol/L)
versus the reference serum creatinine
level. AKI was further classied by stage
according to this ratio (stage I 150199%,
stage II 200299%, stage III $300%).
Stage III AKI was also dened by a serum
creatinine increase of $4.0 mg/dL
($353.6 mmol/L). For each patient, we
considered only the rst episode of AKI.
We performed sensitivity analyses
with two other denitions of AKI using
different reference serum creatinine
values (i.e., either the rst serum creatinine value during hospitalization or the
lowest serum creatinine value during
the year before hospitalization). We also
evaluated whether censoring the death
events that occurred within 1 month after
AKI would modify the results.
Clinical Outcomes

We studied all-cause, cardiovascular, and

noncardiovascular (including cancer-related

and infection-related) deaths, major cardiovascular and cerebrovascular events,

and renal failure (i.e., sustained doubling
of serum creatinine level or end-stage renal disease [ESRD]).
Cardiovascular death was dened as
death due to causes listed in the World
Health Organization ICD-10 (chapter IX).
The cause of death was dened according to the death certicate or hospital
record.
The diagnosis of stroke was adjudicated in patients with focal neurological
abnormalities associated with ischemic
or hemorrhagic tissular lesions found on
computed tomography scan and/or
MRI.
Amputation was dened by a lower limb
amputation above the metatarsophalangeal
joint.
We also recorded revascularization of
the carotid artery (i.e., angioplasty, bypass grafting, or endarterectomy of
carotid artery), revascularization of coronary arteries (angioplasty, coronary artery bypass grafting or coronary stent),
and revascularization of peripheral arteries (angioplasty or bypass of aortic
or lower limb arteries).
Major adverse cardiac events (MACEs)
were dened as a composite end point
(e.g., rst occurrence of cardiovascular
death, nonfatal myocardial infarction,
or nonfatal stroke).
Serum creatinine level doubling was
dened as a sustained (over 1 month)
doubling of serum creatinine level compared with the baseline value. ESRD was
dened by the need for long-term renal
replacement therapy (dialysis or renal
transplantation).
Adjudication Procedure

Living status, cardi ovascular end

points, cerebrovascular end points,
renal failure, and the cause of death
were individually determined from
patients hospital records, French
death certicate registries, biochemical data, and interviews with their
general practitioners, every second
year since 2007. An independent adjudication committee reviewed every
prospectively collected event (10).
Each end point was reviewed by two
independent physicians, and, in case
of disagreement (11.1% of events),
the end point was discussed by the
whole committee until agreement
was found.

care.diabetesjournals.org

Statistical Analyses

Quantitative data were expressed as the

mean 6 SD or median (interquartile
range [IQR]). Qualitative variables are
given as number (percentage) of patients.
Comparisons were conducted using a
t test or Wilcoxon test for normally and
non-normally distributed continuous variables, respectively. Comparisons for categorical variables were performed with
x2 or Fisher exact tests.
Kaplan-Meier curves were plotted to
assess survival. We analyzed data by Cox
proportional hazards models. AKI was
used as a time-dependent variable. A
stepwise descending procedure was
used to determine every nal multivariate model, as follows. All conventional
variables were included in the models,
as follows: eGFR, smoking, albuminuria,
history of myocardial infarction, stroke,
peripheral vascular disease, amputation
in addition to AKI, eGFR and/or albuminuria. All univariate signicant variables
were included in a maximized multivariate
model, then we determined an optimized
model with a backward procedure.
Integrated discrimination improvement (IDI) was calculated to quantify
improvement in model performance after the addition of AKI in the models
(established with a multivariate model).
All hypotheses were tested at the 5%
level of signicance. Statistical analyses
were carried out using the SAS version
9.3 software package (SAS Inc, Cary, NC).
RESULTS
Baseline Characteristics of the
Population

Among the 1,468 type 2 diabetes patients enrolled in the SURDIAGENE cohort, 1,371 participants (58% men) were
considered for the present analysis. We
excluded 97 patients because 22 had
reached ESRD at baseline, and 75 patients had no creatinine measurement
during the follow-up.
Baseline characteristics of the study
population are shown in Table 1. During
the observation period (20022011), full
hospitalization occurred at least once in
984 patients, and the total number of
hospitalizations was 3,660. Overall,
12,456 serum creatinine determinations
were available during the follow-up.
Overall, 43%, 35%, and 22% of patients
had normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively; eGFR was .60 mL/min/1.73 m2

Monseu and Associates

Table 1Baseline characteristics of the study population

Variables

All
(n = 1,371)

Sex, n (%)
Men
Women

794 (58)
577 (42)

268 (65)
143 (35)

526 (55)
434 (45)

Age (years)
African ethnicity, n (%)

65.2 6 10.6
31 (2)

69.1 6 9.6
8 (2)

63.5 6 10.6
23 (2)

,0.0001
0.6081

Follow-up duration (month)

57.3 6 35.1

62.4 6 31.2

55.1 6 36.4

0.0004

BMI (kg/m2)

31.4 6 6.3

31.4 6 6.7

31.4 6 6.1

0.9994

144 (11)

43 (11)

101 (11)

0.9141

14.5 6 10.0

17.4 6 10.5

13.2 6 9.6

,0.0001

7.8 6 1.5

7.9 6 1.5

7.7 6 1.5

0.0197

HbA1c (mmol/mol)

61.7 6 16.4

62.8 6 16.4

60.7 6 16.4

0.0197

Serum creatinine (mmol/L)

eGFR (mL/min/1.73 m2)

82 (32)
73.6 6 23.9

94 (46)
64.0 6 24.6

79 (27)
77.7 6 22.4

,0.0001
,0.0001

uACR (mg/mmol)

3.0 (12.0)

7.7 (33.9)

2.3 (6.8)

,0.0001

Medical history at baseline, n (%)

Myocardial infarction
Stroke
Peripheral artery disease
Amputation
Diabetic retinopathy

210 (15)
79 (6)
309 (23)
69 (5)
549 (41)

82 (20)
31 (8)
128 (31)
38 (9)
203 (50)

128 (13)
48 (5)
181 (19)
31 (3)
346 (37)

0.0018
0.0632
,0.0001
,0.0001
,0.0001

Active smoking, n (%)

Diabetes duration (years)
HbA1c (%)

AKI
No AKI
(n = 411; 30%) (n = 960; 70%)

P value
0.0003

Systolic blood pressure (mmHg)

132.3 6 17.7

135.7 6 18.7

130.9 6 17.0

,0.0001

Diastolic blood pressure (mmHg)

Total cholesterol (mmol/L)

72.3 6 11.2
4.8 6 1.1

72.7 6 11.7
4.8 6 1.1

72.2 6 10.9
4.7 6 1.1

0.4585
0.2897

Resting heart rate (bpm)

73.3 6 13.4

73.4 6 13.7

73.2 6 13.3

0.8839

Treatments, n (%)
Antiplatelet drug
Vitamin K antagonists
Antihypertensive drugs
Diuretics
ARB/ACEI
Antidiabetic agents
Metformin
Sulfonylureas
Glitazones
Glycosidase inhibitors
Insulin
NSAIDs
Lipid-lowering drugs

581 (43)
175 (13)
1,144 (83)
633 (46)
871 (64)
1,316 (96)
653 (48)
550 (40)
16 (1)
79 (6)
820 (60)
40 (3)
807 (59)

202 (49)
84 (20)
378 (92)
223 (54)
283 (69)
399 (97)
149 (36)
136 (33)
1 (0)
18 (4)
296 (72)
14 (3)
253 (62)

379 (40)
91 (10)
766 (80)
410 (43)
588 (61)
917 (96)
504 (53)
414 (43)
15 (2)
61 (6)
524 (55)
26 (3)
554 (58)

0.0011
,0.0001
,0.0001
0.0001
0.0073
0.1776
,0.0001
0.0004
0.0505
0.1460
,0.0001
0.4897
0.1846

Quantitative variables are described by mean 6 SD or median (IQR), unless otherwise

indicated. ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin 2 receptor blocker;
bpm, beats per minute; NSAID, nonsteroidal anti-inammatory drug.

in 73% of patients, between 30 and

59 mL/min/1.73 m 2 in 22% of patients, and ,30 mL/min/1.73 m2 in 5%
of patients.
Median follow-up was 69 months
(IQR 3690). At least one AKI episode
developed in 411 patients (total number
838 AKI episodes; stage I 80%; stage II
14%; stage III 6%). The median number
of hospitalizations before the development of AKI was 2 (range 116, IQR 14)
in the AKI group, and 2 (range 117, IQR
13) in the non-AKI group.
Compared with subjects without AKI
(hospitalized or not), those in whom AKI
developed were older and more frequently

male, and had a longer duration of

diabetes, a lower eGFR, a higher uACR,
and a more frequent cardiovascular history (Table 1).
AKI as a Predictor of All-Cause,
Cardiovascular, and
Noncardiovascular Death

During follow-up, 281 (29%) patients

died. Annual mortality was 43 (IQR 38
48) per 1,000 patient-years. The causes of
death were adjudicated as follows: cardiovascular events (n = 157), cancer (n = 45),
infection (n = 22), and other causes (n = 57).
Survival rate was signicantly lower in
patients with AKI than in those without

Acute Kidney Injury and Outcomes in Diabetes

AKI (log rank = 92.5, P , 0.0001), and

survival rates were signicantly lower in
patients with AKI stage II or stage III than
in those with AKI stage I (Supplementary
Fig. 1A). Similar results were found for
cardiovascular and noncardiovascular
death (Supplementary Fig. 1B and Fig. 1C).
Albuminuria, eGFR, AKI, and the Risk
of All-Cause, Cardiovascular, and
Noncardiovascular Death

When we considered AKI and eGFR together, we observed that both AKI and
low eGFR increased the risk of all-cause
death (Fig. 1A); the same held true for AKI
and albuminuria when considered together
(Fig. 1B). Similar ndings were observed
for cardiovascular death (Fig. 1C and D).
Baseline eGFR, albuminuria, and AKI
were all signicantly associated with the
risk of all-cause and cardiovascular

Diabetes Care

death in the univariate analysis and in

multivariate models (Table 2). In the
univariate analysis, AKI was associated
with an increased risk of noncardiovascular death, including cancer-related or
infection-related deaths (Table 2). Albuminuria was signicantly associated
with cancer-related death, whereas
low eGFR was signicantly associated
with infection-related death during
follow-up (Table 2).
In multivariate models, AKI and albuminuria remained signicantly associated with noncardiovascular deaths.
Only AKI remained signicantly associated with cancer-related death after
multiple adjustments (Table 2). For
infection-related death, adjustments on
AKI, albuminuria, and eGFR could not
be adequately tested due to a lack of
power.

Adding the presence of AKI to established risk factors in the multivariate

model improved the prediction of allcause mortality, as shown by the significant improvement of IDI (20.02, P ,
0.0001). Similarly, prognosis signicantly improved for cardiovascular and
noncardiovascular deaths (IDI = 0.02 [P ,
0.0001] and IDI = 0.02 [P = 0.0004],
respectively).
Sensitivity Analyses

When using alternate denitions of AKI,

results were grossly unchanged (see Supplementary Data, Sensitivity analyses).
Of note, the median time from AKI to
the event was 10 months (range 071
months) for all-cause death, 13 months
(range 071) for cardiovascular death,
and 10 months (range 067 months)
for noncardiovascular death. Overall,

Figure 1Combined risk of all-cause death and cardiovascular death associated with eGFR and development of AKI (A and C), and albuminuria and
the development of AKI (B and D) considered together. Circle and lines indicate hazard ratio point estimates and 95% CIs. Labels on the lines
represent hazard ratio estimates. AKI was diagnosed according to the KDIGO criteria as serum creatinine value increase .150% or $0.3 mg/dL
($26.5 mmol/L) vs. baseline serum creatinine level. Albuminuria categories were dened as follows: normoalbuminuria, uACR ,3 mg/mmol;
microalbuminuria, uACR $3 and # 30 mg/mmol; and macroalbuminuria, uACR .30 mg/mmol. Normoalbuminuria was present in 681 patients
(50%), microalbuminuria was present in 467 patients(34%), and macroalbuminuria was present in 218 patients (16%). eGFR was .60 mL/min/1.73 m2
for 998 patients (73%), between 30 and 60 mL/min/1.73 m2 for 298 patients (22%), and ,30 mL/min/1.73 m2 for 75 patients (5%). The estimates were
adjusted for baseline covariates, including smocking status and log uACR (A), smocking status and eGFR (B), and history of myocardial infarction and
log uACR (C), and they were nonadjusted (D). All the parameters were signicant as follows: for A: AKI (P , 0.0001), eGFR stages (P , 0.0001), and
interaction between AKI and eGFR stages (P , 0.0001); for B: AKI (P , 0.0001), albuminuria categories (P , 0.0001), and interaction between
AKI and albuminuria categories (P = 0.0008); for C: AKI (P , 0.0001), eGFR stages (P , 0.0001), and interaction between AKI and eGFR stages
(P = 0.0116); and for D: AKI (P , 0.0001), albuminuria categories (P , 0.0001), and interaction between AKI and albuminuria categories (P = 0.0354).
alb., albuminuria; HR, hazard ratio. (A high-quality color representation of this gure is available in the online issue.)

care.diabetesjournals.org

Monseu and Associates

Table 2AKI, eGFR, and albuminuria as predictors of death

Univariate
HR

95% CI

P value

,0.0001 5.53
,0.0001 0.92
,0.0001 1.38

4.247.21
0.870.97
1.191.59

,0.0001
0.0033
,0.0001

Cardiovascular deaths
AKI (yes vs. no)
7.43 5.3310.37 ,0.0001 4.81
eGFR (per 10 mL/min/1.73 m2) 0.74 0.700.79 ,0.0001 0.87
Albuminuria (log mg/mmol) 2.13 1.802.52 ,0.0001 1.46

3.396.82
0.810.94
1.201.77

,0.0001
0.0002
0.0002

4.359.51

,0.0001

1.051.57

0.0167

All-cause deaths
AKI (yes vs. no)
7.38
eGFR (per 10 mL/min/1.73 m2) 0.80
Albuminuria (log mg/mmol) 1.88

95% CI

Multivariate*
P value

5.769.46
0.770.84
1.662.13

HR

Noncardiovascular deaths
AKI (yes vs. no)
7.31 5.0310.63 ,0.0001 6.43
0.0014
eGFR (per 10 mL/min/1.73 m2) 0.89 0.830.96
Albuminuria (log mg/mmol) 1.60 1.321.94 ,0.0001 1.28

Cancer-related deaths
AKI (yes vs. no)
5.85 3.1310.93 ,0.0001 5.80 3.0810.90 ,0.0001
0.5438
eGFR (per 10 mL/min/1.73 m2) 0.96 0.851.09
Albuminuria (log mg/mmol) 1.43 1.031.99
0.0326
Infection-related deaths
AKI (yes vs. no)
9.98 4.0624.53 ,0.0001
0.0062
eGFR (per 10 mL/min/1.73 m2) 0.79 0.670.94
Albuminuria (log mg/mmol) 1.46 0.912.35
0.1128
During follow-up, 281 (29%) patients died: causes of death were cardiovascular (n = 157), cancer
(n = 45), infection (n = 22) and other (n = 57). HR, hazard ratio. *A stepwise descending procedure
was used to determine every nal multivariate model: All-cause death, optimized model
adjusted for AKI, eGFR, albuminuria, and smoking status; Cardiovascular deaths, optimized
model adjusted for AKI, eGFR, albuminuria, and history of myocardial infarction;
Noncardiovascular death, optimized model adjusted for AKI, albuminuria, and smoking status;
Cancer-related deaths, optimized model adjusted for AKI and smoking status.

23 deaths (11 cardiovascular/12 noncardiovascular deaths) occurred within

the rst month after AKI: when these
events were censored, the results were
qualitatively unchanged (see Supplementary Data, Sensitivity analyses and
Supplementary Table 1).
AKI, Albuminuria, eGFR, and Major
Vascular Outcomes

During follow-up, vascular events were

registered as follows: hospitalization for
heart failure (n = 157, 16%), myocardial
infarction (n = 81, 8%), stroke (n = 55,
6%), lower limb amputation (n = 54, 6%),
lower-limb revascularization (n = 60,
6%), coronary artery revascularization
(n = 101, 10%), carotid artery revascularization (n = 25, 3%), and MACE
(n = 238, 17%).
In univariate analysis, AKI, eGFR, and
albuminuria were associated with MACE,
hospitalization for heart failure, myocardial infarction, stroke, lower limb amputation, lower limb revascularization, and
coronary artery revascularization during
follow-up. Only AKI was signicantly associated with carotid artery revascularization (Table 3).
Using multivariate analyses, AKI was associated with all of the major cardiovascular

outcomes, whereas eGFR and albuminuria

were inconstantly associated with these
outcomes (Table 3).
AKI, Low eGFR, and Albuminuria as
Predictors of Renal Risk

Renal failure (i.e., sustained doubling of

serum creatinine level or ESRD) occurred
in 79 patients (8%) during follow-up.
Time to renal failure was signicantly
associated with AKI (log rank 19.2, P ,
0.0001).
As expected, AKI, eGFR, and albuminuria were associated with renal
failure in univariate and multivariate
analyses when these three renal parameters were entered into the models
(Table 3).
CONCLUSIONS

In the present prospective inception cohort, we adjudicated causes of death

(cardiovascular, cancer, infection, or
other causes) and major cardiovascular
and renal events in subjects with type 2
diabetes. We carefully analyzed the
prognostic value of AKI, low eGFR, and
abnormal albuminuria alone or in combination on relevant diabetes-related
events. The two major ndings of the
study were as follows: 1) AKI was a

powerful predictor of all-cause death,

noncardiovascular and cardiovascular
deaths, and all major cerebrovascular,
cardiovascular, and renal events; and
2) AKI, low eGFR, and albuminuria remained predictors of all-cause and cardiovascular deaths, even when considered
simultaneously.
In the current study, we observed for
the rst time that AKI predicted the risk
of all-cause death and cardiovascular
death in a cohort specically dedicated
to patients with type 2 diabetes. Similar
data were observed in other populations, notably after myocardial infarction or coronary revascularization (13).
To the best of our knowledge, our study
is also the rst to demonstrate a strong
and robust relationship between AKI
and noncardiovascular death. Surprisingly, we found that AKI was associated
with cancer-related and infection-related
death.
Furthermore, AKI predicted the risk of
chronic nonfatal myocardial infarction,
hospitalization for heart failure, lower
limb amputation and revascularization,
carotid and coronary revascularization,
nonfatal stroke, and renal failure. The
risk of subsequent coronary events or
stroke was increased in patients with
AKI in most studies (8,14,15). A greater
risk of hospitalization for heart failure
after myocardial infarction or percutaneous coronary revascularization procedure was also noted (7,8). However,
we were able to identify other major
consequences of AKI such as lower
limb amputation and revascularization, or carotid revascularization.
The results of our study extend the
relationship between AKI and adverse
outcomes even further to patients with
diabetes and to all relevant major cardiovascular and noncardiovascular
events that we have analyzed. These
ndings are important because the incidence of cardiovascular and cerebrovascular events remains greater in
patients with diabetes compared with
patients without diabetes, although
the number of major complications declined from 1990 to 2010 (1). Moreover,
patients with diabetes also have a
greater risk of cancer and infection
than subjects without diabetes (2,3).
The need for reliable and simple risk
sensors is thus of outmost importance in
diabetes. Importantly, AKI remained a signicant marker of outcome regardless of

Acute Kidney Injury and Outcomes in Diabetes

Diabetes Care

Table 3AKI, eGFR, and albuminuria as predictors of major events

Univariate
HR

95% CI

Multivariate*
95% CI

P value

,0.0001 2.97
,0.0001 0.89
,0.0001 1.33

2.233.95
0.840.94
1.131.56

,0.0001
,0.0001
0.0005

5.079.87
0.720.81
1.742.44

,0.0001 4.69
,0.0001 0.91
,0.0001 1.49

3.306.66
0.840.98
1.221.82

,0.0001
0.0086
0.0001

Myocardial infarction
AKI (yes vs. no)
2.90
eGFR (per 10 mL/min/1.73 m2) 0.80
Albuminuria (log mg/mmol) 1.70

1.744.82
0.740.88
1.342.15

,0.0001 1.98
,0.0001 0.85
,0.0001

1.173.36
0.780.93

0.0116
0.0002

Stroke
AKI (yes vs. no)
2.49
eGFR (per 10 mL/min/1.73 m2) 0.87
Albuminuria (log mg/mmol) 1.40

1.344.61
0.780.97
1.031.88

2.35

1.264.38

0.0070

Lower limb amputation

AKI (yes vs. no)
15.60
eGFR (per 10 mL/min/1.73 m2) 0.77
Albuminuria (log mg/mmol) 2.45

8.528.8
0.690.85
1.843.25

,0.0001 10.5
,0.0001
,0.0001 1.65

5.719.6

,0.0001

1.212.25

0.0016

Peripheral artery
revascularization
AKI (yes vs. no)
4.93
eGFR (per 10 mL/min/1.73 m2) 0.86
Albuminuria (log mg/mmol) 1.81

2.808.67
0.780.96
1.372.38

,0.0001 3.56
0.0059
,0.0001 1.49

1.986.43

,0.0001

1.112.00

0.0078

Carotid artery revascularization

AKI (yes vs. no)
7.23
eGFR (per 10 mL/min/1.73 m2) 0.90
Albuminuria (log mg/mmol) 1.37

3.0617.09 ,0.0001 6.10 2.5614.52 ,0.0001

0.761.05 0.1675
0.882.13 0.1674

Coronary artery
revascularization
AKI (yes vs. no)
2.30
eGFR (per 10 mL/min/1.73 m2) 0.88
Albuminuria (log mg/mmol) 1.31

1.403.80
0.820.96
1.051.64

Doubling serum creatinine level/

ESRD
AKI (yes vs. no)
6.97
eGFR (per 10 mL/min/1.73 m2) 0.57
Albuminuria (log mg/mmol) 6.22

4.3811.1
0.510.63
4.708.22

MACE
AKI (yes vs. no)
4.35
eGFR (per 10 mL/min/1.73 m2) 0.79
Albuminuria (log mg/mmol) 1.81

3.305.73
0.750.83
1.582.08

Heart failure requiring

hospitalization
AKI (yes vs. no)
7.07
eGFR (per 10 mL/min/1.73 m2) 0.77
Albuminuria (log mg/mmol) 2.06

P value

0.0039
0.0119
0.0294

0.0011
0.0022
0.0166

HR

2.04

1.233.39

0.0055

,0.0001 2.47
,0.0001 0.78
,0.0001 4.23

1.504.05
0.700.87
3.075.83

0.0004
,0.0001
,0.0001

During follow-up, the following major events were noted: hospitalization for heart failure (n = 157),
myocardial infarction (n = 81), stroke (n = 55), lower limb amputation (n = 54), lower limb
revascularization (n = 60), coronary artery revascularization (n = 101), carotid artery
revascularization (n = 25), and renal failure (i.e., sustained doubling of serum creatinine or ESRD)
(n = 79). HR, hazard ratio. *A stepwise descending procedure was used to determine every nal
multivariate model: MACE, optimized model adjusted for AKI, eGFR, albuminuria, history of
myocardial infarction and amputation; Heart failure requiring hospitalization, optimized model
adjusted for AKI, eGFR, albuminuria, history of myocardial infarction and lower limb
arteriopathy; Myocardial infarction, optimized model adjusted for AKI, eGFR and history of lower
limb arteriopathy; Stroke, optimized model adjusted for AKI and history of stroke; Lower limb
amputation, optimized model adjusted for AKI, albuminuria and history of amputation; Lower limb
revascularization, optimized model adjusted for AKI, albuminuria and history of lower limb arteriopathy;
Carotid revascularization, optimized model adjusted for AKI and history of lower limb arteriopathy;
Coronary revascularization, optimized model adjusted for AKI and history of lower limb arteriopathy;
Doubling serum creatinine level/ESRD, optimized model adjusted for AKI, eGFR, and albuminuria.

its denition and severity. We used a

well-accepted denition of AKI (12),
and we performed sensitivity analyses
using different denitions of AKI: our results remained qualitatively unchanged.
We also assessed whether AKI severity

modied our results: we observed a

dose-effect relationship between the severity of AKI and the risk of all-cause and
cardiovascular deaths, but not for the
risk of renal failure, even though the
smaller number of the latter outcomes

might lead to inadequate statistical

power.
The exact mechanisms explaining the
association between AKI and subsequent major deleterious outcomes are
unknown. AKI may be associated with
systemic inammation. Immediately after experimental AKI, alarmins, tumor
necrosis factor-a, interleukin-1, and
interleukin-6 are produced; and lead to
activation and proliferation of immune
cells, deterioration of renal function
through the development of interstitial brosis, tubular atrophy, and glomerular sclerosis. Production of these
substances may also have systemic
consequences, including reduced left
ventricular fractional and myocardial
cell apoptosis (9,16,17). Systemic production of proinammatory cytokines
associated with AKI may be responsible, at least in part, for the increased
risk of renal, cardiovascular, and noncardiovascular events (16).
Alternatively, the occurrence of AKI
may be a marker of renal and overall
frailty in these patients with diabetes,
since AKI was associated with age, duration of diabetes, blood pressure, and
vascular diseases in our study and in
the literature (18). This is supported by
the association between AKI and noncardiovascular death such as cancer
death or infection death.
The other major nding of our study,
which may be one of the most salient
ones, is the fact that AKI, eGFR, and albuminuria, even when simultaneously
considered, remained signicantly associated with all-cause and cardiovascular
death and heart failure. It has been
known for several years that eGFR and
albuminuria considered together are
powerful predictors of all-cause and cardiovascular deaths (19). In a recent
study (20), albuminuria in addition to
B-type natriuretic peptide emerged
as a key biomarker predicting the risk
of heart failure. In patients from the
Atherosclerosis Risk in Communities
study, cystatin C levels and elevated albuminuria were associated with a further risk of cardiovascular events,
including heart failure (21). Interestingly, albuminuria was frequently observed and was a predictor of death in
patients with heart failure in the GISSIHF study (22). Our results indicate that
all three renal markers have prognostic
value in diabetes: AKI can be used alone

care.diabetesjournals.org

or in addition to eGFR and albuminuria

to predict cardiovascular events, including heart failure. Taken together, these
results suggest that the information regarding the risk of death or cardiovascular death conveyed by these renal
markers is not redundant.
Interestingly, AKI was a predictor of
renal failure and, when simultaneously
considered, AKI, low eGFR, and albuminuria remained signicant predictors and
rened the estimation of the risk of renal failure in subjects with diabetes. Although low GFR and microalbuminuria/
macroalbuminuria remained powerful
predictors of all-cause death and cardiovascular death, even after adjustment
for AKI, AKI seemed the most powerful
biomarker of major events.
Admittedly, our study has several limits. We did not focus our analysis on the
exact cause of AKI. However, most of
our cases of AKI were stage I, which
could result from many situations, including sepsis, dehydration, or use of
nephrotoxic medications. It was not
possible to assess whether the cause
of AKI could play a role in our ndings.
Although our end points considered
cardiovascular and renal outcomes,
which are major in diabetes, other
relevant diabetic microvascular end
points, such as retinopathy or neuropathy, were not studied. In addition,
only AKI in inpatients were considered.
AKI in outpatients may have different
predictive value on outcomes. However, to our knowledge, this type of
analysis has not been performed in
the literature.
Finally, the results of our monocentric
study need to be replicated.
Our study has also some strengths. It
is a relatively large prospective study
with a long-term follow-up. Of note,
85% of studies reporting the long-term
consequences of AKI were retrospective
in a recent meta-analysis (13). In the
present report, an independent committee adjudicated all events of interest,
and records were individually handled
and reviewed using hospital discharge
summaries, interviews with general
practitioners, and biochemical data.
This point is probably crucial, although
rarely performed in the literature:
most studies only use administrative
records to determine clinical outcomes,
although this method was recently
questioned (23,24).

Monseu and Associates

To our knowledge, the current study

is also the rst to examine the risk for
death, cardiovascular events, and noncardiovascular events in a comprehensive way in relation to AKI, albuminuria,
and eGFR, considered separately or together, and the rst one evaluating the
long-term risk of AKI in consecutively
recruited patients with diabetes.
In conclusion, AKI is a powerful predictor of major cerebrovascular, cardiovascular, and noncardiovascular events
and deaths in individuals with type 2 diabetes. All three renal markers (AKI,
eGFR, and albuminuria) alone or considered together are synergistically predictors of total and cardiovascular deaths,
and renal outcomes.

Acknowledgments. The authors thank all pa-

tients followed up for their kind participation in

this research and the adjudication committee of
the SURDIAGENE study.
Funding. The SURDIAGENE study was supported by grants from the French Minister of
Health (PHRC-Poitiers 2004 and PHRC-IR 2008)
and AFD (Research Grant 2003). Groupe dEtude
des Maladies M e taboliques et Syst e miques
(Poitiers, France) supported the current study.
Duality of Interest. No potential conicts of
interest relevant to this article were reported.
The funders had no involvement in study
design, or in the collection, analyses, and interpretation of the data.
Author Contributions. M.M. searched the
literature, constructed the gures, wrote and
edited the article, and contributed to the discussion. E.G. performed the statistical analysis,
constructed the gures, edited the article, and
contributed to the discussion. P.-J.S., S.R., X.P.,
P.Z., V.R., R.M., and R.R. edited the article and
contributed to the discussion. S.H. designed the
study, proposed the current analysis, searched
the literature, wrote and edited the article, and
contributed to the discussion. J.-M.H. proposed
the current analysis, searched the literature,
wrote and edited the article, and contributed to
the discussion. J.-M.H. is the guarantor of this work
and, as such, had full access to all the data in the
study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.

References
1. Gregg EW, Li Y, Wang J, et al. Changes in
diabetes-related complications in the United
States, 1990-2010. N Engl J Med 2014;370:
15141523
2. Muller LM, Gorter KJ, Hak E, et al. Increased
risk of common infections in patients with
type 1 and type 2 diabetes mellitus. Clin Infect
Dis 2005;41:281288
3. Michels KB, Solomon CG, Hu FB, et al.;
Nurses Health Study. Type 2 diabetes and subsequent incidence of breast cancer in the
Nurses Health Study. Diabetes Care 2003;26:
17521758

4. Mogensen CE. Microalbuminuria predicts

clinical proteinuria and early mortality in
maturity-onset diabetes. N Engl J Med 1984;
310:356360
5. Go AS, Chertow GM, Fan D, McCulloch CE,
Hsu CY. Chronic kidney disease and the risks of
death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:12961305
6. Lo LJ, Go AS, Chertow GM, et al. Dialysisrequiring acute renal failure increases the risk
of progressive chronic kidney disease. Kidney
Int 2009;76:893899
7. James MT, Ghali WA, Knudtson ML, et al.;
Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH)
Investigators. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation
2011;123:409416
8. Chawla LS, Amdur RL, Shaw AD, Faselis C,
Palant CE, Kimmel PL. Association between AKI
and long-term renal and cardiovascular outcomes in United States veterans. Clin J Am Soc
Nephrol 2014;9:448456
9. Chawla LS, Eggers PW, Star RA, Kimmel PL.
Acute kidney injury and chronic kidney disease
as interconnected syndromes. N Engl J Med
2014;371:5866
10. Hadjadj S, Fumeron F, Roussel R, et al.;
DIABHYCAR Study Group; DIAB2NEPHROGENE
Study Group; SURDIAGENE Study Group. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic
subjects: results from the Non-insulin-dependent
Diabetes, Hypertension, Microalbuminuria or
Proteinuria, Cardiovascular Events, and Ramipril
(DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE),
and Survie, Diabete de type 2 et Genetique
(SURDIAGENE) studies. Diabetes Care 2008;
31:18471852
11. Levey AS, Stevens LA, Schmid CH, et al.;
CKD-EPI (Chronic Kidney Disease Epidemiology
Collaboration). A new equation to estimate glomerular ltration rate. Ann Intern Med 2009;
150:604612
12. Kellum JA, Lameire N; KDIGO AKI Guideline
Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1). Crit Care 2013;17:204
13. Coca SG, Yusuf B, Shlipak MG, Garg AX,
Parikh CR. Long-term risk of mortality and other
adverse outcomes after acute kidney injury: a
systematic review and meta-analysis. Am J Kidney Dis 2009;53:961973
14. Rihal CS, Textor SC, Grill DE, et al. Incidence
and prognostic importance of acute renal failure
after percutaneous coronary intervention. Circulation 2002;105:22592264
15. Wu V-C, Wu C-H, Huang T-M, et al.; NSARF
Group. Long-term risk of coronary events after
AKI. J Am Soc Nephrol 2014;25:595605
16. Ratliff BB, Rabadi MM, Vasko R, Yasuda K,
Goligorsky MS. Messengers without borders:
mediators of systemic inammatory response
in AKI. J Am Soc Nephrol 2013;24:529536
17. Wencker D, Chandra M, Nguyen K, et al. A
mechanistic role for cardiac myocyte apoptosis
in heart failure. J Clin Invest 2003;111:14971504
18. James MT, Hemmelgarn BR, Wiebe N, et al.;
Alberta Kidney Disease Network. Glomerular ltration rate, proteinuria, and the incidence and

Acute Kidney Injury and Outcomes in Diabetes

consequences of acute kidney injury: a cohort

study. Lancet 2010;376:20962103
19. Matsushita K, van der Velde M, Astor BC,
et al.; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular ltration rate and albuminuria with all-cause and
cardiovascular mortality in general population
cohorts: a collaborative meta-analysis. Lancet
2010;375:20732081
20. Velagaleti RS, Gona P, Larson MG, et al.
Multimarker approach for the prediction of

Diabetes Care

heart failure incidence in the community. Circulation 2010;122:17001706

21. Matsushita K, Sang Y, Ballew SH, et al. Cardiac and kidney markers for cardiovascular prediction in individuals with chronic kidney disease: the
Atherosclerosis Risk in Communities study. Arterioscler Thromb Vasc Biol 2014;34:17701777
22. Masson S, Latini R, Milani V, et al.; GISSI-HF
Investigators. Prevalence and prognostic value
of elevated urinary albumin excretion in patients with chronic heart failure: data from the

GISSI-Heart Failure trial. Circ Heart Fail 2010;3:

6572
23. Grams ME, Waikar SS, MacMahon B,
Whelton S, Ballew SH, Coresh J. Performance
and limitations of administrative data in the
identication of AKI. Clin J Am Soc Nephrol
2014;9:682689
24. Vlasschaert MEO, Bejaimal SAD, Hackam
DG, et al. Validity of administrative database
coding for kidney disease: a systematic review.
Am J Kidney Dis 2011;57:2943